Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a high incidence of neuropsychiatric involvement. Signs and symptoms of neuropsychiatric SLE (NPSLE) are among the earliest and most common manifestations in lupus patients, and can occur independently of non-neurologic disease. In the MRL/lpr strain as well, a commonly used murine lupus model, behavioral changes consistent with severe depression and impaired cognition are evident in young animals before increased autoantibody titers and other major organ involvement. These and other studies indicate that NPSLE is indeed a primary disease manifestation. Nevertheless, despite the high prevalence of NPSLE and its poor prognosis, the pathogenesis is not well understood and optimal treatment is still unclear. Previous studies have largely focused on potential etiological factors such as autoantibodies and neurodegeneration that often become apparent only relatively late after onset of SLE. These factors do not adequately explain the early onset of NPSLE observed in lupus mice or in many patients. Among putative regulators of early CNS dysfunction, cytokines can both directly and indirectly promote negative CNS outcomes via a range of different mechanisms. These include effects on autoantibodies, increasing secretion of cytokines and other inflammatory mediators, loss of integrity of the blood brain barrier (BBB), and alteration of neurotransmitter metabolism. Members of the TNF superfamily are important in the pathogenesis of SLE. TWEAK is a secreted member of this cytokine superfamily, with pleotropic effects on multiple cell types, including promotion of inflammation and context-dependent effects on cell survival and apoptosis. The TWEAK receptor, Fn14, is expressed in astrocytes, microglia, brain microvascular endothelial cells, and neurons. Furthermore, TWEAK induces the release of other inflammatory cytokines known to play a role in NPSLE. Recently, we found that Fn14 deficient MRL/lpr lupus mice display significantly less depression and cognitive abnormalities than Fn14 sufficient MRL/lpr littermates, while human NPSLE is associated with high TWEAK levels in the CSF. Our preliminary studies strongly support the hypotheses that 1) TWEAK plays a major role in the etiology of NPSLE; 2) TWEAK blockade may be a novel approach for the treatment of neuropsychiatric disease. In this proposal, we will confirm the role of TWEAK in the pathogenesis of NPSLE, examine the mechanisms by which TWEAK signaling induces neurobehavioral abnormalities in lupus, and study the therapeutic potential of TWEAK inhibition for treating manifestations of NPSLE.